Co-crystals occur in nature and form spontaneously with closely related chemical structures, such as chemical isomers (racemates, diasteriomers, and the like). Co-crystals are also found for materials that complex together in solution such as protein-ligands, chelates, inclusion complexes as with cyclodextrins, and ligands. In U.S. Pat. Nos. 4,971,797; 6,312,723 and 6,312,712, complexes of cyclodextrin and active agents are described as being co-crystallized together from solution. These complexes lack the flexibility to incorporate materials with broadly different chemical structures and lack the multi-functional properties that mixed co-crystals can impart.
In certain cases, macromolecules (both polymers and biopolymers) are capable of forming co-crystals with other macromolecules. These co-crystallized products have been used to isolate macromolecules such as proteins for structural characterization. An example of this is found in the paper by Murphy et al. (Acta Crystallogr D Biol Crystallogr, 55(Pt 9), 1594-1597 (1999)). These simple co-crystals are not useful to enhance solubility, dissolution or absorption of poorly absorbed active agents.
Minor amounts of materials can be incorporated in a particle sub-structure. These components co-exist with crystalline phases of the particle and produce co-crystalline regions within the particle. The resulting co-crystallized material has a high level of crystallinity and lacks significant amounts of amorphous phase. Examples of these applications can be found in patents describing the dilution of sweetening agents in sugar carriers as in U.S. Pat. Nos. 6,214,402 and 6,365,216. Incorporation of small amounts of single constituents differs from mixed phase co-crystals since the particles produced do not have a significant amount of amorphous phase as indicated by melting properties and solubility. In addition, these materials do not contain an active agent, lack the high concentrations that the mixed phase co-crystals enable, and lack the multi-functional aspects that mixed phase co-crystals offer with respect to improved drug delivery.
Co-crystallization of chemically related materials is illustrated by the preparation of co-crystallized sugars (U.S. Pat. Nos. 4,101,680 and 4,338,339), of acetylenic compounds (U.S. Pat. No. 4,384,980), and sugar alcohols (U.S. Pat. Nos. 5,679,398; 5,958,471 and 6,083,438). The simple co-crystals therein described do not have the broad utility that mixed phase co-crystals have for the enhancement of properties of widely different structures and physico-chemical properties.
Incorporation of minor components by a process described as ‘co-crystallization’ that yields a product of indeterminate crystalline structure is illustrated by U.S. Pat. Nos. 6,376,481, and 6,267,963 (sterol esters); U.S. Pat. No. 6,214,402 (dilution of sweetener); U.S. Pat. No. 4,751,294 (stabilization by a base); U.S. Pat. No. 5,910,523 (nanocomposites); U.S. Pat. No. 5,876,506 (mesomorphic sugar), U.S. Pat. No. 5,075,291 (uniform dispersion of drug in sugar alcohol); and U.S. Pat. No. 5,451,416. These materials of indeterminate structure lack the ability of mixed phase co-crystals to maintain primary crystalline characteristics of the active agent while imparting amorphous-like properties along with designed functionalities to enhance solubility, dissolution, and absorption.
Complex mixtures of crystalline materials formed by melt/congealing process are described in U.S. Pat. No. 6,267,963 (sterol-emulsion complexes); U.S. Pat. Nos. 4,855,326 and 5,853,762 (rapidly dissolving dosage unit); and U.S. Pat. No. 5,075,291. The process for preparing co-crystals by evaporation or cooling from a solvent system is described in U.S. Pat. No. 4,145,214 (photoconductors); U.S. Pat. Nos. 4,751,294; 4,971,797; and 6,214,402. Applications for which no active agent is incorporated are described in U.S. Pat. Nos. 4,145,214 and 4,384,980. These materials of indeterminate structure lack the ability of mixed phase co-crystals to maintain primary crystalline characteristics of the active agent while imparting amorphous-like properties along with designed functionalities to enhance solubility, dissolution, and absorption.
In the field of active agent delivery, inherent problems associated with the active agent exist, such as particle size, stability, solubility, powder physical properties and release rates. New and improved methods to solve the problems associated with active agent delivery are needed. The invention provides such a method, as well as mixed phase co-crystal compositions comprising an active agent. These and other advantages of the invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.